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Original Investigation
April 20, 2022

Cerebrospinal Fluid Biomarkers in Patients With Unipolar Depression Compared With Healthy Control Individuals: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
  • 2Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
JAMA Psychiatry. 2022;79(6):571-581. doi:10.1001/jamapsychiatry.2022.0645
Key Points

Question  Are there differences in cerebrospinal fluid (CSF) biomarkers between patients with unipolar depression and healthy control individuals?

Findings  In this systematic review and meta-analysis of 97 studies, CSF levels of interleukin 6, total protein, and cortisol were higher among patients with unipolar depression, whereas levels of homovanillic acid, γ-aminobutyric acid, somatostatin, brain-derived neurotrophic factor, amyloid-β 40, and transthyretin were lower. However, the number of eligible studies was limited for most of the identified biomarkers, and analyses revealed substantial heterogeneity among studies.

Meaning  This study found numerous biomarkers in the CSF were altered in individuals with unipolar depression, indicating a multifactorial pathogenesis implicating several neurocircuits; however, high-quality studies investigating multiple CSF markers are needed.


Importance  Depression has been associated with alterations in neurotransmitters, hormones, and inflammatory and neurodegenerative biomarkers, and biomarkers quantified in the cerebrospinal fluid (CSF) are more likely to reflect ongoing biochemical changes within the brain. However, a comprehensive overview of CSF biomarkers is lacking and could contribute to the pathophysiological understanding of depression.

Objective  To investigate differences in quantified CSF biomarkers in patients with unipolar depression compared with healthy control individuals.

Data Sources  PubMed, EMBASE, PsycINFO, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for eligible trials from database inception to August 25, 2021.

Study Selection  All studies investigating CSF biomarkers in individuals 18 years and older with unipolar depression and healthy control individuals were included. One author screened titles and abstracts, and 2 independent reviewers examined full-text reports. Studies that did not include healthy control individuals or included control individuals with recent hospital contacts or admissions that might affect CSF biomarker concentrations were excluded.

Data Extraction and Synthesis  Data extraction and quality assessment were performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Meta-analyses were performed using standardized mean differences (SMDs) calculated with random-effects models. A third investigator was consulted if the 2 reviewers reached different decisions or when in doubt.

Main Outcomes and Measures  Quantifiable CSF biomarkers.

Results  A total of 167 studies met eligibility criteria, and 97 had available data and were included in the meta-analysis. These 97 studies comprised 165 biomarkers, 42 of which were quantified in 2 or more studies. CSF levels of interleukin 6 (7 studies; SMD, 0.35; 95% CI, 0.12 to 0.59; I2 = 16%), total protein (5 studies; SMD, 0.53; 95% CI, 0.35 to 0.72; I2 = 0%), and cortisol (2 studies; SMD, 1.23; 95% CI, 0.89 to 1.57; I2 = 0%) were higher in patients with unipolar depression compared with healthy control individuals, whereas homovanillic acid (17 studies; SMD, −0.26; 95% CI, −0.39 to −0.14; I2 = 11%), γ-aminobutyric acid (4 studies; SMD, −0.50; 95% CI, −0.92 to −0.08; I2 = 55%), somatostatin (5 studies; SMD, −1.49; 95% CI, −2.53 to −0.45; I2 = 91%), brain-derived neurotrophic factor (3 studies; SMD, −0.58; 95% CI, −0.97 to −0.19; I2 = 0%), amyloid-β 40 (3 studies; SMD, −0.80; 95% CI, −1.14 to −0.46; I2 = 0%), and transthyretin (2 studies; SMD, −0.82; 95% CI, −1.37 to −0.27; I2 = 0%) were lower. The remaining 33 biomarkers had nonsignificant results.

Conclusions and Relevance  The findings of this systematic review and meta-analysis point toward a dysregulated dopaminergic system, a compromised inhibitory system, hypothalamic-pituitary-adrenal axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology.

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    1 Comment for this article
    Psychological injuries can account for multifactorial pathogenesis
    Eric Kuelker, Ph.D. | Private Practice
    Keller and Neale interviewed 4,856 people multiple times over a dozen years. They found that 88% of depressive episodes were the result of a stressful life event, such as divorce, demotion, or major financial stress. What is notable is that each type of event had a specific pattern of symptoms. The symptoms for romantic loss had a specific profile, which was distinct for the symptom pattern for financial stress. Depression has high heterogeneity because the type of life events and their resultant symptoms are distinct from each other. The issue is not so much about 'several neurocircuits' the issue is the type of loss, abuse, or stress that the person experienced. Keller, Neale, Kendler (2007) Am J Psychiatry. Oct;164(10):1521-9.